Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_002880.3(RAF1):c.775T>A (p.Ser259Thr)

CA261617

40601 (ClinVar)

Gene: RAF1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 70e55828-a26c-447c-863d-156419f819e2

HGVS expressions

NM_002880.3:c.775T>A

NM_002880.3(RAF1):c.775T>A (p.Ser259Thr)

NC_000003.12:g.12604195A>T

CM000665.2:g.12604195A>T

NC_000003.11:g.12645694A>T

CM000665.1:g.12645694A>T

NC_000003.10:g.12620694A>T

NG_007467.1:g.64985T>A

NM_001354689.1:c.775T>A

NM_001354690.1:c.775T>A

NM_001354691.1:c.532T>A

NM_001354692.1:c.532T>A

NM_001354693.1:c.676T>A

NM_001354694.1:c.532T>A

NM_001354695.1:c.433T>A

NR_148940.1:n.1190T>A

NR_148941.1:n.1190T>A

NR_148942.1:n.1190T>A

NM_001354689.3:c.775T>A

NM_001354690.2:c.775T>A

NM_001354691.2:c.532T>A

NM_001354692.2:c.532T>A

NM_001354693.2:c.676T>A

NM_001354694.2:c.532T>A

NM_001354695.2:c.433T>A

NR_148940.2:n.1106T>A

NR_148941.2:n.1106T>A

NR_148942.2:n.1106T>A

ENST00000251849.8:c.775T>A

ENST00000416093.1:c.*353T>A

ENST00000423275.5:c.*452T>A

ENST00000432427.2:n.412T>A

ENST00000442415.6:c.775T>A

ENST00000465826.5:n.19T>A

ENST00000491290.1:n.296T>A

Pathogenic

PS4_Supporting PM5_Strong PM6_Strong PS3 PM2 PM1 PP1 PP3 PP2

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.775T>A (p.Ser259Thr) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; APHP-Robert Debré Hospital internal data; GTR ID's: 28338). The p.Ser259Thr variant has been identified in at least 8 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381 PMID: 21784453; ClinVar SCV000061360.5; SCV000209017.10). The p.Ser259Thr variant in RAF1 has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 506381; ClinVar SCV000209017.9). In vitro functional studies provide some evidence that the p.Ser259Thr variant may impact protein function (PS3; PMID: 21784453, 20052757). At least 2 other pathogenic missense variants have been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40603, 40602, 228288). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Ser259Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Supporting, PP1, PM5_Strong, PM2, PM1, PP2, PP3, PS3.

PS4_Supporting

The p.Ser259Thr variant has been identified in at least 8 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381 PMID: 21784453; ClinVar SCV000061360.5; SCV000209017.10).

PM5_Strong

At least 2 other pathogenic missense variants have been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40603, 40602, 228288).

PM6_Strong

PS3

In vitro functional studies provide some evidence that the p.Ser259Thr variant may impact protein function (PS3; PMID: 21784453, 20052757).

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).

Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). PubMed:29493581

PP1

The p.Ser259Thr variant in RAF1 has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; GeneDx, Zenker et al. internal data; ClinVar SCV000209017.9).

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP2

The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581).

Approved on: 2017-04-03

Published on: 2020-04-13

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